A systematic review and meta-analysis of second-line therapies for treatment of mesothelioma

Open ArchivePublished:July 02, 2018DOI:https://doi.org/10.1016/j.rmed.2018.06.026

      Highlights

      • Malignant pleural mesothelioma is treated with platinum/pemetrexed 1st line therapy.
      • We performed a systematic review and meta-analysis of 49 s line studies.
      • Median PFS and OS were 3.4 and 7.8 months.
      • The pooled overall response rate was 8.6%.
      • There remains uncertainty about the ideal second-line agent for pleural mesothelioma.

      Abstract

      Introduction

      Advanced malignant pleural mesothelioma (MPM) is generally treated with platinum/pemetrexed-based first-line therapy. Once the disease progresses, evidence for the efficacy of palliative treatments is lacking, and platinum re-challenge or single-agent chemotherapy are commonly used. To assess the effects of cytostatic or targeted therapy for treating MPM, we performed a systematic review and meta-analysis.

      Material and methods

      PubMed, the Cochrane Library, and Embase databases were searched to identify published articles on second-line treatments for recurrent or advanced mesothelioma. Inclusion criteria were publication in the English language, describing clinical trials with 20 or more patients, and evaluability for efficacy and for receiving second-line systemic therapies. Data were pooled using number of events/number of evaluable patients, median overall survival (OS) and progression-free survival (PFS), according to a fixed or random effect model. Pooled median OS was the primary endpoint.

      Results

      A total of 49 eligible studies (n = 3938 patients; range, 12–400) were identified. Median progression-free survival (PFS) was 3.4 months (95%CI 2.87–3.93). Median pooled OS was 7.86 (95%CI 7.01–8.72). The pooled overall response rate (ORR) was 8.63% (95%CI 6–11.26), and the pooled disease control rate (DCR) was 54.8% (95%CI 48.9–60.6). Median pooled OS with platinum- and pemetrexed-based chemotherapy were 7.93 and 7.78 months, respectively.

      Conclusions

      There remains uncertainty about the ideal second-line agent for MPM. Based on this meta-analysis, palliative chemotherapy or other experimental agents can be considered for patients with MPM who desire further treatment after their disease has progressed, during or after first-line therapy.

      Keywords

      1. Introduction

      Malignant pleural mesothelioma is a rare neoplasm that arises from the mesothelial surfaces of the pleural cavity. It generally has poor prognosis, with a median survival of four to 13 months for untreated patients, and six to 18 months for treated patients, regardless of the therapeutic approach [
      • Ong S.T.
      • Vogelzang N.J.
      Chemotherapy in malignant pleural mesothelioma: a review.
      ]. Primary debulking surgery is reserved for those with resectable disease, limited to one emithorax. Otherwise, for all other patients, palliative chemotherapy, with platinum-based chemotherapy (including pemetrexed) is typically prescribed and increases overall survival (OS) by roughly three months, compared to single-agent cisplatin, in cases where disease is either unresectable, or where patients are not otherwise candidates for potentially curative surgery [
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      ]. Recently, the addition of bevacizumab to this standard doublet has increased OS by 2.7 months, compared to cisplatin/pemetrexed only [
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      ].
      Once the disease recurs, the are no approved standard drugs or regimens for second-line therapy. Rechallenging using the same upfront therapy, platinum-based therapy including gemcitabine or other single-agent chemotherapies (gemcitabine, vinca alkaloids, or anthracyclines), or enrollment in clinical trials are possible treatment options. The most extensive data pertaining to second-line settings is derived from pemetrexed, which can increase progression-free survival (PFS), but not OS, compared to best supportive care only [
      • Jassem J.
      • Ramlau R.
      • Santoro A.
      • et al.
      Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.
      ]. On the other hand, interesting new data have become available regarding targeted therapies and immunotherapy.
      Due to the limited availability of relevant data from randomised trials, summarising the available evidence of second-line therapies for malignant pleural mesothelioma can increase insight into whether chemotherapy and targeted therapies are potentially suitable for pre-treated individuals with advanced disease. We have designed this meta-analysis with the aim to aggregate the largest number of existing studies employing salvage therapies. We also performed sub-group analyses wherever possible to investigate whether the overall results were consistent across sub-sets of treatments and participants, due to the possible heterogeneity of the included studies in terms of intervention and participant groups.

      2. Material and methods

      2.1 Search strategy and inclusion criteria

      PubMed, the Cochrane Library, and Embase databases were searched to identify published articles on second-line treatment for recurrent or advanced mesothelioma. The search used the terms ‘mesothelioma’ and (‘second-line’ OR (‘recurrent’ or ‘relapsed’ or ‘progressed’))). Inclusion criteria were publication in the English language, describing clinical trials with 20 or more patients evaluable for efficacy and whit data available for efficacy of second-line systemic therapies. Publications in other languages or those that were available only in abstract form were excluded. Case reports or small case series were also excluded, as were pre-clinical studies or reviews, and studies adopting locoregional treatments alone, or that were associated with systemic agents, were also excluded. A manual review of the references of retrieved articles was performed to locate additional relevant publications.

      2.2 Data extraction and statistical analysis

      Data describing the demographics of the patient population treated, as well as the efficacy of all treatments, were extracted from the included studies by one author (FP), and then reviewed by a second author (AG) to ensure accuracy. Discrepancies were discussed with a third author for consensus. The demographic characteristics of patients treated consisted of country, median age, and previous platinum-based chemotherapy for advanced disease. Response rate (RR), defined as the sum of complete (CR) and partial (PR) responses, disease control rate (DCR), defined as the sum of RR and stable disease (SD), median progression-free survival (PFS) or time-to-progression (TTP), as well as median OS, with their 95% confidence intervals (95% CI), were considered efficacy outcomes of interest, and were extracted from the included publications. Weights for each study in the analysis were based on individual sample sizes. Pooled median OS was the primary endpoint.
      Descriptive statistics were computed for the outcome measures. Heterogeneity amongst studies was evaluated with Cochran's Q and I2 tests. The fixed-effect model was used when between-study heterogeneity was low. Alternatively, when heterogeneity was moderate or high, a random-effect model was used for calculation of the pooled summary statistics [
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ].
      A sub-group analysis was performed to highlight any differences between publications with different agents (chemotherapy vs. targeted therapies), TTP from previous first-line therapy (>vs. <6 months), histology (epithelioid vs. others), type of chemotherapy (platinum-based and pemetrexed-based), and year of publication (with meta-regression analysis). Publication bias was assessed using Begg's and Egger's tests with funnel plots [
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias author ( s ): Colin B. Begg and Madhuchhanda Mazumdar published by : international Biometric society stable.
      ,
      • Stuck A.E.
      • Rubenstein L.Z.
      • Wieland D.
      • et al.
      Bias in meta-analysis detected by a simple, graphical.
      ]. Calculations were performed using Meta-Essentials [
      • Suurmond R.
      • van Rhee H.
      • Hak T.
      Introduction, Comparison, and Validation of Meta-Essentials : a free and simple tool for meta-analysis.
      ].

      3. Results

      The electronic search and the review of reference lists identified a total of 1014 records for screening (Fig. 1). After screening and eligibility assessment, a total of 49 eligible studies (n = 3938 patients; range 12–400) were identified [
      • Jassem J.
      • Ramlau R.
      • Santoro A.
      • et al.
      Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.
      ,
      • Zucali P.A.
      • Perrino M.
      • Lorenzi E.
      • et al.
      Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.
      ,
      • Zucali P.A.
      • Simonelli M.
      • Michetti G.
      • et al.
      Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey.
      ,
      • Zucali P.A.
      • Ceresoli G.L.
      • Garassino I.
      • et al.
      Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.
      ,
      • Zauderer M.G.
      • Kass S.L.
      • Woo K.
      • Sima C.S.
      • Ginsberg M.S.
      • Krug L.M.
      Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.
      ,
      • Toyokawa G.
      • Takenoyama M.
      • Hirai F.
      • et al.
      Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy.
      ,
      • Xanthopoulos A.
      • Bauer T.T.
      • Blum T.G.
      • Kollmeier J.
      • Schönfeld N.
      • Serke M.
      Gemcitabine combined with oxaliplatin in pretreated patients with malignant pleural mesothelioma: an observational study.
      ,
      • Wheatley-Price P.
      • Chu Q.
      • Bonomi M.
      • et al.
      A phase II study of PF-03446962 in patients with advanced malignant pleural mesothelioma. CCTG trial IND.207.
      ,
      • Calabrò L.
      • Morra A.
      • Fonsatti E.
      • et al.
      Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
      ,
      • Steer J.
      • Bough G.
      • Razak A.R.A.
      • Meachery G.J.
      • Hughes A.
      Life after first-line chemotherapy in malignant pleural mesothelioma: a north-east england experience.
      ,
      • Stebbing J.
      • Powles T.
      • McPherson K.
      • et al.
      The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma.
      ,
      • Tourkantonis I.
      • Makrilia N.
      • Ralli M.
      • et al.
      Phase II study of gemcitabine plus docetaxel as second-line treatment in malignant pleural mesothelioma.
      ,
      • Reck M.
      • Stahel R.A.
      • von Pawel J.
      • et al.
      Pemetrexed in the treatment of malignant mesothelioma: results from an expanded access program in Germany.
      ,
      • Raynaud C.
      • Greillier L.
      • Mazieres J.
      • et al.
      Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study).
      ,
      • Santoro A.
      • O'Brien M.E.
      • Stahel R.A.
      • et al.
      Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the international expanded access program.
      ,
      • Sørensen J.B.
      • Sundstrøm S.
      • Perell K.
      • Thielsen A.-K.
      Pemetrexed as second-line treatment in malignant pleural mesothelioma after platinum-based first-line treatment.
      ,
      • Papa S.
      • Popat S.
      • Shah R.
      • et al.
      Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-Containing chemotherapy.
      ,
      • Pasello G.
      • Nicotra S.
      • Marulli G.
      • et al.
      Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience.
      ,
      • Ramalingam S.S.
      • Belani C.P.
      • Ruel C.
      • et al.
      Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma.
      ,
      • Porta C.
      • Zimatore M.
      • Bonomi L.
      • et al.
      Raltitrexed-oxaliplatin combination chemotherapy is inactive as second-line treatment for malignant pleural mesothelioma patients.
      ,
      • Mutlu H.
      • Gündüz Ş Karaca H.
      • et al.
      Second-line gemcitabine-based chemotherapy regimens improve overall 3-year survival rate in patients with malignant pleural mesothelioma: a multicenter retrospective study.
      ,
      • Nowak A.K.
      • Millward M.J.
      • Creaney J.
      • et al.
      A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma.
      ,
      • Manegold C.
      • Symanowski J.
      • Gatzemeier U.
      • et al.
      Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.
      ,
      • Janne P.A.
      • Wozniak A.J.
      • Belani C.P.
      • et al.
      Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.
      ,
      • Jackman D.M.
      • Kindler H.L.
      • Yeap B.Y.
      • et al.
      Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma.
      ,
      • Nowak A.K.
      • Brown C.
      • Millward M.J.
      • et al.
      A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced malignant pleural mesothelioma.
      ,
      • Krug L.M.
      • Kindler H.L.
      • Calvert H.
      • et al.
      Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.
      ,
      • Kostron A.
      • Friess M.
      • Crameri O.
      • et al.
      Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma.
      ,
      • Laurie S.A.
      • Gupta A.
      • Chu Q.
      • et al.
      Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC clinical trials group.
      ,
      • Giaccone G.
      • O'Brien M.E.R.
      • Byrne M.J.
      • Bard M.
      • Kaukel E.
      • Smit B.
      Phase II trial of ZD0473 as second-line therapy in mesothelioma.
      ,
      • Maio M.
      • Scherpereel A.
      • Calabrò L.
      • et al.
      Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
      ,
      • Laurie S.A.
      • Hao D.
      • Leighl N.B.
      • et al.
      A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group.
      ,
      • Garland L.L.
      • Chansky K.
      • Wozniak A.J.
      • et al.
      Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509.
      ,
      • Gunduz S.
      • Mutlu H.
      • Goksu S.S.
      • et al.
      Oral cyclophosphamide and etoposide in treatment of malignant pleural mesothelioma.
      ,
      • Gregorc V.
      • Zucali P.A.
      • Santoro A.
      • et al.
      Phase II study of asparagine-glycine-arginine-human tumor necrosis factor α, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma.
      ,
      • Dubey S.
      • Jänne P.A.
      • Krug L.
      • et al.
      A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307.
      ,
      • Dudek A.Z.
      • Pang H.
      • Kratzke R.A.
      • et al.
      Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a Brief report.
      ,
      • Fennell D.A.
      • McDowell C.
      • Busacca S.
      • et al.
      Phase II clinical trial of first or second-line treatment with Bortezomib in patients with malignant pleural mesothelioma.
      ,
      • Fennell D.A.
      • Steele J.P.C.
      • Shamash J.
      • et al.
      Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesothelioma.
      ,
      • Campbell N.P.
      • Kunnavakkam R.
      • Leighl N.
      • et al.
      Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium.
      ,
      • Dogan M.
      • Utkan G.
      • Hocazade C.
      • et al.
      The clinicopathological characteristics with long-term outcomes in malignant mesothelioma.
      ,
      • Ceresoli G.L.
      • Zucali P.A.
      • De Vincenzo F.
      • et al.
      Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma.
      ,
      • Calabrò L.
      • Morra A.
      • Fonsatti E.
      • et al.
      Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.
      ,
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      ,
      • Bearz A.
      • Talamini R.
      • Rossoni G.
      • et al.
      Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience.
      ,
      • Beebe-Dimmer J.L.
      • Fryzek J.P.
      • Yee C.L.
      • et al.
      Mesothelioma in the United States: a surveillance, epidemiology, and end results (SEER)–medicare investigation of treatment patterns and overall survival.
      ,
      • Özyılkan Ö.
      Malignant pleural mesothelioma: a single-center experience in Turkey.
      ,
      • Scherpereel A.
      • Berghmans T.
      • Lafitte J.J.
      • et al.
      Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study.
      ].
      Publication data ranged from 2005 to 2018. Two were observational studies, two were expanded access programme studies, one was a phase 1b study, 28 were phase two studies, 3 were phase three studies, and 13 were retrospective series. All studies except one (Chinese population) included Caucasian subjects treated in Western countries. Among the agents used as second-line therapies, two were immunotherapies (in n = 3 studies), 18 were targeted therapies (in n = 18 studies), and 28 publications included various chemotherapy regimens. A summary of the characteristics of the included studies is provided in Table 1.
      Table 1Characteristics of included studies.
      Author/yearType of studyCountryNumber of patientsMedian age/2nd line %Previous platinum-based-CT (%)Treatment (n)RR (%)CBR (%)PFS (months)OS (months)
      Alley/2017Phase 1bInternational2565/6088Pembrolizumab20725.418
      Bearz/2012RetrospectiveItaly3064/100100PEM [
      • Zucali P.A.
      • Perrino M.
      • Lorenzi E.
      • et al.
      Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.
      ] or platinum/PEM [
      • Raynaud C.
      • Greillier L.
      • Mazieres J.
      • et al.
      Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study).
      ]
      17675.1 (TTP)13.6
      Beebe-dimmer/2016RetrospectiveUS172-/100100
      of 114 patients treated with platinum.
      GEM [
      • Krug L.M.
      • Kindler H.L.
      • Calvert H.
      • et al.
      Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.
      ] or platinum/PEM [
      • Jackman D.M.
      • Kindler H.L.
      • Yeap B.Y.
      • et al.
      Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma.
      ]; other [
      • Campbell N.P.
      • Kunnavakkam R.
      • Leighl N.
      • et al.
      Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium.
      ]
      5
      Calabro/2013Phase 2Italy2964/100100Tremelimumab6.9316.210.7
      Calabro/2015Phase 2Italy2965/100100Tremelimumab1386.211.3
      Campbell/2012Phase 2US50-/88Cediranib10441.84.4
      Ceresoli/2011Observational studyItaly3165/58100PEM [
      • Wheatley-Price P.
      • Chu Q.
      • Bonomi M.
      • et al.
      A phase II study of PF-03446962 in patients with advanced malignant pleural mesothelioma. CCTG trial IND.207.
      ] or platinum/PEM [
      • Calabrò L.
      • Morra A.
      • Fonsatti E.
      • et al.
      Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
      ]
      19483.8
      Dogan/2014RetrospectiveTurkey32-/10083CDDP/PEM or CDDP/GEM or GEM or PEM17.439.5
      Dubey/2010Phase 2US30-/100Sorafenib3.333.713.2
      Dudek/2012Phase 2US4668/100100Dasatanib5332.276.5
      Fennel/2006Phase 2UK1356/1007.7CPT-11 + CDDP + MMC30 (n = 10)807.37.3
      Fennel/2012Phase 2Europe2365/100Bortezomib4.8 (n = 21)9.62.1 (TTP)5.78
      Garland/2011Phase 2US4766.8/100100Cediranib9 (n = 43)432.569.5
      Giaccone/2012Phase 2International4759/100ZD04730 (n = 43)55.82.75 (TTP)7.25
      Gregorc/2010Phase 2Italy4766/100100NGR-hTNF 3w and w2462.812.1
      Gregorc/2018Phase 3International40065/100100NGR-hTNF vs investigator choice + BSC59 (n = 186)°3.4°8.5°
      Gunduz/2014RetrospectiveTurkey2255/100100Oral CTX + VP1618.272.77.728.1
      Jackman/2008Phase 2US2462.5/10080Erlotinib + bevacizumab0502.2 (TTP)5.8
      Janne/2006EAPUS18766/100 ≥2nd linePEM or CDDP/PEM19.658.27.1
      Jassem/2008Phase 3International12360/100PEM + BSC18.759.33.68.4
      Kostron/2016RetrospectiveSwitzerland48-/100100CDDP/PEM [
      • Nowak A.K.
      • Brown C.
      • Millward M.J.
      • et al.
      A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced malignant pleural mesothelioma.
      ]; CDDP/GEM [
      • Zucali P.A.
      • Perrino M.
      • Lorenzi E.
      • et al.
      Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.
      ]; VRB [
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      ]; PEM [
      • Ong S.T.
      • Vogelzang N.J.
      Chemotherapy in malignant pleural mesothelioma: a review.
      ]; GEM [
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      ]; CBDCA [
      • Jassem J.
      • Ramlau R.
      • Santoro A.
      • et al.
      Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.
      ]
      9 (PRS)
      Krug/2015Phase 3International32964/77PEM 97%Vorinostat11.57.6
      Laurie/2011Phase 2Canada1765/64100Sunitinib0642.88.3
      Laurie/2017Phase 2Canada1267/67100Dovitinib12.5 (n = 8)75 (n = 8)2.64
      Maio/2017Randomized phase 2bInternational38266/63PEM 99%Tremelimumab4.527.72.87.7
      Mutlu/2014RetrospectiveTurkey3356.4/100100GEM11.3
      Nowak/2012Phase 2Australia5166/100100Sunitinib12773.5 (TTP)6.1
      Nowak/2013Phase 2Australia3064/100100BNC105P461.58.2
      Papa/2013Phase 2UK5366/100100Sorafenib625.19
      Pasello/2011RetrospectiveItaly1561/76100CDDP/GEM [
      • Zucali P.A.
      • Simonelli M.
      • Michetti G.
      • et al.
      Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey.
      ] or CBDCA/GEM [
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      ]
      673.7 (TTF)7
      Porta/2005Phase 2Italy1459.5/10035.6Raltitrexed + Oxaliplatin028.51.863.26
      Ramalingan/2009Phase 2US1373/9253.8Belinostat015.315
      Raynaud/2015RetrospectiveFrance16268.9/10091GEM ± VNR/PEM/Platinum624.6NRNR
      Reck/2008EAPGermany21363/100PEM ± CDDP (155)/PEM + CBDCA [
      • Scherpereel A.
      • Wallyn F.
      • Albelda S.M.
      • Munck C.
      Novel therapies for malignant pleural mesothelioma.
      ]
      16695.6 (TTP)8.6
      Scherpereel/2011Phase 2France4569/100100Valproate + doxorubicin16362.56.7
      Scott/2011Phase 2Canada1765/100Sunitinib0642.88.3
      Sezer/2014RetrospectiveTurkey54-/37CDDP + PEM [
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ] or GEM [
      • Zauderer M.G.
      • Kass S.L.
      • Woo K.
      • Sima C.S.
      • Ginsberg M.S.
      • Krug L.M.
      Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.
      ]/MMM [
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      ]
      NR7.6612.03
      Sorensen/2007Phase 2Denmark/Norway3962/92100PEM [
      • Pasello G.
      • Nicotra S.
      • Marulli G.
      • et al.
      Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience.
      ]/PEM + CBDCA [
      • Zucali P.A.
      • Ceresoli G.L.
      • Garassino I.
      • et al.
      Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.
      ]
      20NR5.6 (TTP)9.4
      Stebbing/2009Phase 2UK6359/100VRB1684NR9.6
      Steer/2010RetrospectiveUK6262/4296PEM + Platinum (19)/VRB [
      • Ong S.T.
      • Vogelzang N.J.
      Chemotherapy in malignant pleural mesothelioma: a review.
      ]/
      43626.54.6
      MMC + VLB + CDDP [
      • Ong S.T.
      • Vogelzang N.J.
      Chemotherapy in malignant pleural mesothelioma: a review.
      ]
      Taylor/2008EAPInternational39663/100100PEM/PEM + Platinum12.158.14.9NR
      Toyokawa/2014Phase 2Japan1758/100100GEM + VRB18826.011.2
      Tourkantonis/2011Phase 2Greece3766/100100GEM + DTX18.981.17.0 (TTP)16.2
      Wheatley-Price/2008Phase 2Canada1768/100100PF-03446962013.331.7NR
      Xanthopoulos/2008ObservationalGermany2965/51100Oxaliplatin ± GEM6.944.82.1716.7
      Zauderer/2014RetrospectiveUS6067/6293GEM [
      • Wheatley-Price P.
      • Chu Q.
      • Bonomi M.
      • et al.
      A phase II study of PF-03446962 in patients with advanced malignant pleural mesothelioma. CCTG trial IND.207.
      ]/VRB [
      • Nowak A.K.
      • Brown C.
      • Millward M.J.
      • et al.
      A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced malignant pleural mesothelioma.
      ]/GEM + VRB(12)
      1.7 (n = 56)47.21.665.21
      Zhang/2010Phase 2China5352/64100PEM + Platinum13.281.16.010.0
      Zucali/2008Phase 2Italy3066/10080GEM + VRB10.043.32810.9
      Zucali/2012RetrospectiveItaly18164/10092PEM ± Platinum (61)/11.652.64.38.7
      Platinum ± VRB [
      • Stuck A.E.
      • Rubenstein L.Z.
      • Wieland D.
      • et al.
      Bias in meta-analysis detected by a simple, graphical.
      ] or GEM(13)
      CBDCA + PAC [
      • Ong S.T.
      • Vogelzang N.J.
      Chemotherapy in malignant pleural mesothelioma: a review.
      ]/VRB(14)/GEM [
      • Tourkantonis I.
      • Makrilia N.
      • Ralli M.
      • et al.
      Phase II study of gemcitabine plus docetaxel as second-line treatment in malignant pleural mesothelioma.
      ]/VRB + GEM [
      • Raynaud C.
      • Greillier L.
      • Mazieres J.
      • et al.
      Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study).
      ]
      Other [
      • Dudek A.Z.
      • Pang H.
      • Kratzke R.A.
      • et al.
      Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a Brief report.
      ]
      Zucali/2014RetrospectiveItaly5969/57VRB15.249.12.36.2
      + pemetrexed-based CT; RR: response rate; CBR: clinical benefit rate; PFS: progression free survival; OS: overall survival; TTP: time to progression; TTF: time to treatment failure; PRS: median postrecurrence survival; EAP: expanded access program; PEM: pemetrexed; GEM: gemcitabine; CDDP: cisplatin; CPT-11: irinotecan; MMC: mitomycin C; CTX: cyclophosphamide; VP16: etoposide; VNR: vinorelbine; CBDCA: carboplatin; VLB: vinblastine; 3 M: mitoxantrone + methotrexate + mitomycin; DTX: docetaxel; PAC: paclitaxel; BSC: best supportive care; °, only experimental arm considered.
      of 114 patients treated with platinum.

      3.1 Progression-free and overall survival

      Pooled PFS and OS were obtained from n = 40 and 41 studies, respectively. Heterogeneity was high and as a result, a random effect model was used for pooling. Median PFS was 3.4 months (95%CI 2.87–3.93; P for heterogeneity <0.001, I2 = 0.87) (Fig. 2).
      Fig. 2
      Fig. 2Polled analysis of progression-free survival (PFS); CI:confidence interval.
      Median pooled OS was 7.86 (95%CI 7.01–8.72; P for heterogeneity <0.001, I2 = 0.85) (Fig. 3). According to sub-group analysis, there was a trend for a better median OS with immunotherapy, compared to targeted therapies and chemotherapies (10.75 vs. 7.32 vs. 8.35 months; P for difference = 0.18). Effect size (OS) did not vary during the years, with no improvement from 2005 to 2017 (P = 0.41), according to meta-regression analysis. Median pooled OS with platinum-based and pemetrexed-based chemotherapy were 7.93 and 7.78 months, respectively.
      Fig. 3
      Fig. 3Polled analysis of overall survival (OS); CI:confidence interval.
      The effectiveness according to TTP of first-line therapy and histology was not calculated, because only four and one studies reported these data, respectively.

      3.2 Overall response rate and disease-control rate

      Fourty and 42 studies had data available for ORR and DCR, respectively. The pooled ORR was 8.63% (95%CI 6–11.26; P for heterogeneity <0.001, I2 = 0.95; Fig. 4), and pooled DCR was 54.9% (95%CI 49.3–60.4; P for heterogeneity <0.001, I2 = 0.86).
      Fig. 4
      Fig. 4Polled analysis of overall response rate; CI:confidence interval.

      3.3 Publication bias

      A funnel plot for publication bias shows evidence of some bias for both Begg's and Egger's tests (P = 0.005 for both analyses) (Fig. 5).
      Fig. 5
      Fig. 5Funnel plot for publication bias in overall survival analysis.

      4. Discussion

      While the combination of cisplatin and pemetrexed is the standard first-line therapy for malignant mesothelioma of the pleura, there are no approved agents for second-line or further salvage settings. Recently, the addition of bevacizumab to six cycles of first-line chemotherapy, and continued thereafter as maintenance, further extended median OS by two months in the MAPS study, and may represent the new standard of care for chemonaive pleural mesothelioma [
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      ]. The benefit of second-line therapy is described in the phase three study that compared platinum/pemetrexed vs. platinum only, where post-study chemotherapy reduced the risk of death by 44% [
      • Manegold C.
      • Symanowski J.
      • Gatzemeier U.
      • et al.
      Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.
      ].
      In this meta-analysis of 49 studies, including only three randomised studies and several single-arm phase two studies, the pooled median OS and PFS were roughly 8 and 3.5 months, with an ORR and DCR of 8% and 55%, respectively. Among tested agents, immunotherapies were the most promising, with a trend for better median OS (3.5 and 2.5 months more), compared to chemotherapy or other targeted therapies. Immunotherapy using checkpoint inhibitors may represent a more effective therapy for the control of disease in pre-treated patients. For example, in Alley et al., treatment with anti-programmed cell death 1 (PD-1) antibody pembrolizumab resulted in five partial responses and 13 patients with stabilised disease, for an overall DCR of 72% and an ORR of 20% [
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      ]. The role of pemetrexed rechallenge was also explored in a second-line therapy in patients with good performance status, particularly after response to first-line therapy. In our analysis, platinum-based doublets and pemetrexed-based therapy were associated with an ORR of roughly 30% and 18% respectively, but a similar median OS (roughly eight months). The most compelling data about salvage therapy are those regarding pemetrexed only, or with cisplatin, the combination associated with the largest ORR (32% vs. 5%), observed in the expanded access phase 3b study of Janne et al. [
      • Janne P.A.
      • Wozniak A.J.
      • Belani C.P.
      • et al.
      Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.
      ]. In the phase three study of Jassem et al., pemetrexed increased ORR (by 1.7%–18.7%), but was associated with similar OS, compared to best supportive care [
      • Jassem J.
      • Ramlau R.
      • Santoro A.
      • et al.
      Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.
      ].
      In general, the choice of second-line agent depends on several factors: response and TTP with first-line therapy, performance status, and the wishes of the patient. The Third Italian Consensus Conference for Malignant Pleural Mesothelioma [
      • Novello S.
      • Pinto C.
      • Torri V.
      • et al.
      The third Italian Consensus Conference for malignant pleural mesothelioma: state of the art and recommendations.
      ], it was stated that due to a lack of approved agents for second-line treatment, this represents an ideal setting for testing new agents. When enrollment in a clinical trial is not possible, single-agent chemotherapy can be considered for fit patients, even if best supportive care remains an option [
      • Novello S.
      • Pinto C.
      • Torri V.
      • et al.
      The third Italian Consensus Conference for malignant pleural mesothelioma: state of the art and recommendations.
      ]. A similar position is provided in ESMO guidelines, which suggests enrollment in a clinical trial as the preferred option [
      • Baas P.
      • Fennell D.
      • Kerr K.M.
      • van Schil P.E.
      • Haas R.L.
      • Peters S.
      Malignant pleural mesothelioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. The v 2.2017 NCCN version of malignant pleural mesothelioma guidelines indicates that despite single agents such as vinorelbine and pemetrexed rechallenge (in the case of good response after first-line treatment) being options, there are limited data for guiding second-line therapy [
      • Scherpereel A.
      • Wallyn F.
      • Albelda S.M.
      • Munck C.
      Novel therapies for malignant pleural mesothelioma.
      ]. The role of immunotherapy is still growing in cancer as mesothelioma, but preliminary results are intriguing. Despite mesothelioma is associated with a relatively low tumour burdenm and PD-L1 expression is less frequent, exploring immunity pathways is interesting in light of the general modest improvement with standard cytotoxic drugs and for the recognition of the existence of an inflamed state and an immune cell infiltrate in mesothelioma tissue [
      • Scherpereel A.
      • Wallyn F.
      • Albelda S.M.
      • Munck C.
      Novel therapies for malignant pleural mesothelioma.
      ,
      • Patil N.S.
      • Righi L.
      • Koeppen H.
      • et al.
      Molecular and histopathological Characterization of the tumor immune Microenvironment in advanced stage of malignant pleural mesothelioma.
      ]. For these reasons, in the last years a series of clinical trials were designed to exploit the role of immune checkpoint inhibitors in this setting, and our results confirm a positive trend for a better outcome.
      Our meta-analysis has several limitations. First, it is a meta-analysis that included only three randomised studies, and as such, the increased benefit obtained, if any, by second-line therapy was not defined. Second, the meta-analysis included different regimens (including chemotherapy and without chemotherapy), and patients with different disease statuses, comorbidities, and disease burdens, despite the majority having been pre-treated with platinum-based chemotherapy. Third, heterogeneity was high, and the funnel plot showed evidence of publication bias. However, this is nonetheless the most extensive systematic review of all second-line therapies for malignant mesothelioma to date. It includes 49 studies for a total of 3938 patients with previously treated disease, and shows a DCR of more than 50%, even if ORR was <10%. Median OS was similar to historical data using pemetrexed-based chemotherapy (8 months), establishing that outcomes have not been improved during the past decade, as shown by our meta-regression analysis of survival at the time of publication. Finally, this review provides essential landmarks (OS 8 months; PFS 3.5 months) for patients receiving second-line treatment, which can represent a basis for future clinical trials of systemic therapies in progressive/recurrent pleural malignant mesothelioma. This information will be especially useful for studies adopting a single-arm design, or that compare new agents with placebo or supportive care, because no new agent has to date improved OS, compared to observation/no active treatment.
      Second-line studies with innovative agents remain ongoing. In particular, a phase two study with pembrolizumab is recruiting patients with malignant mesothelioma, with the primary endpoint being correlation of PD-L1 with response and secondary endpoints represented by PFS, OS, and DCR [NCT02399371]. One randomised trial are ongoing. The study (a randomised phase two trial) is comparing the efficacy and safety of second or third-line treatment with nivolumab monotherapy and nivolumab plus ipilimumab, for unresectable mesothelioma patients [NCT02716272]. Preliminary results of this study were presented at the 2017 ASCO meeting. In the current study, approximately 17% and 26% of patients who took nivolumab and the combination treatment exhibited reduced tumour size, respectively. Median OS was 10.4 months for nivolumab, but was not reached in the combination arm [
      • Patil N.S.
      • Righi L.
      • Koeppen H.
      • et al.
      Molecular and histopathological Characterization of the tumor immune Microenvironment in advanced stage of malignant pleural mesothelioma.
      ].
      In conclusion, second-line therapies for malignant mesothelioma using chemotherapy or modern drugs in the case of patients previously exposed to platinum-based therapy is moderately effective, with a median OS of about 8 months, a modest response rate (8%), and median PFS (3.4 months). The outcome using salvage therapy has not evolved in the past decade, and the most active combinations appear to be those that are platinum-and/or pemetrexed-based (or immunotherapies), but with a median OS near similar to the effect-size calculated in the global population. In our meta-analysis, the most promising results were obtained using immunotherapy, compared to other targeted agents or chemotherapies. While waiting for the results of ongoing trials, it is hoped that in the near future, novel agents such as immunotherapies may provide meaningful PFS and OS improvements for these patients.

      Conflicts of interest

      The authors declare no conflict of interest.

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